Multiple Sclerosis (MS) in the most common inflamatory disease of the nervous system, manifested by attacks of muscle weakness and loss of coordination, visual disturbances, bladder dysfunction and cognitive impairment. In the United States, MS is ranked as the second leading cause of neurologic disability among young adults, most notably women of childbearing age. For decades, it has been known that women are more susceptible than men to MS but the reasons for this health disparity are unclear. There is also plenty of clinical and experimental evidence that pregnancy lessens MS symptoms. However, women after childbirth suffer a worsening in disease severity. Also, women commonly exhibit the relapsing-remitting form of MS and have fluctuations in disease severity with their menstrual cycle. All this information suggest that female sexual hormones are deeply involved in MS onset and progession and understanding this component of MS is essential for the design of novel therapeutic strategies. Our lab, has found that normal human brain and mouse spinal cord tissues exhibit ablumenal localization of the chemokine CXCL12 at their vasculature. However, specimens from patients with MS and mice with experimental autoimmune encephalomyelitis (EAE) exhibit relocation of CXCL12 to the lumenal surfaces of vessels. This alteration in CXCL12 expression has been shown to impact on the egress immune cells localized in spaces around microvasculature, enhancing disease severity during EAE. In preliminary studies, we have determined that the naive female SJL mouse, which may be induced to develop relapsing-remitting EAE via active immunization, exhibits lumenal CXCL12 expression within the white matter microvasculature, while the naove male SJL mouse, which does not develop relapsing-remitting EAE, exhibits ablumenal CXCL12 within all spinal cord regions. Microarray and corroborating quantitative PCR analysis comparing gray (cortical) and white (cerebellar) matter tissues from naove 10 week-old male and female SJL mice detected significantly 2-fold increased expression of the Sphingosine 1-Phosphate Receptor 2 (S1PR2), also known as Edg-5, in the cerebella of female SJL mice compared with male SJL cerebella and with both male and female SJL cortices. S1PR2 is a member of a G protein-coupled receptor family of endothelial differentiation genes with 8 members. Agonists of S1P receptors have previously been shown to be effective targets for the treatment of EAE and MS, predominantly through immunosuppressive mechanisms. FTY720, an agonist of S1P receptors, is known to cause retention of lymphocytes in lymphoid tissue via the specific activation of S1PR1/Edg-3, inducing lymphopenia in vivo. Furthermore, suppression of S1PR1 signaling by FTY720 has negative effect on CXCR4-mediated lymph node egress. Our preliminary data, however, suggests that an alternative receptor, S1PR2, might be a more specific target for manipulation of BBB biology during brain and spinal cord autoimmunity. In addition, our data reveals that white matter expression of this receptor exhibits sexual dimorphism, which suggests that it might be relevant for the development of relapsing-remitting MS. The central hypothesis of this proposal is that sexually dimorphic expression of S1PR2/Edg-5 impacts on the polarity of CXCL12 expression at the BBB through effects on adherent junction integrity, which, in turn, impacts on sexually dimorphic patterns of disease expression during EAE. PUBLIC HEALTH RELEVANCE: Multiple Sclerosis (MS) in the most common inflamatory disease of the brain and the second leading cause of neurologic disability among young adults, most notably women of childbearing age. For decades, it has been known that women are more susceptible than men to MS but the reasons for this health disparity are unclear. However, many scientist in the field recognize the involvement of female sexual hormones in the initiation and progression of MS and understanding this component is essential for the design of novel therapeutic strategies. Our lab, has found a protein called CXCL12 to play an important role in allowing inflammatory cells to get into the brain. The purpose of this research project is to elucidate the contribution of female sexual hormones in this process.